Group I metabotropic glutamate receptor-triggered temporally patterned action potential-dependent spontaneous synaptic transmission in mouse MNTB neurons

Rhythmic action potentials (AP) exist in life-sustaining centers in the nervous system that control heartbeat, respiration, and locomotion (review in Moore et al., 2014; Del Negro et al., 2018) including newborn's crying (Wei et al., 2022). Neurons in the brainstem reticular formation, where the central control for respiration and heartbeat resides, generate rhythmic spike firing essential for survival during early development. Such rhythmic spike activities maintain for the life span of the organisms. Regulation of neuronal properties and top-down control are the underlying mechanisms of such rhythmogenesis (review in Shamir, 2019). The targets of the rhythmically firing neurons, consequently, receive temporally patterned synchronized neurotransmitter release and thus respond with synaptic activities of regular inter-event intervals (IEIs), to maintain a relatively constant heartbeat and regular breathing. In sensory processing, such patterned activities exist as a specialized neuronal property, such as phase-locking of auditory neurons for precise temporal coding (review in Heil and Peterson, 2017). Alternatively, such temporally patterned spike activities can be induced by artificially manipulating the sensory stimuli in such a way that neural responses lock to the timing of the stimuli with regular IEIs. Interestingly, the rhythm in heartbeat and respiration exerts influences on the sensitivity of somatosensory perception (Grund et al., 2022).

Unlike periodic stimulus-evoked transmitter release, generation of action potential (AP)-dependent spontaneous transmitter release in CNS neurons is considered a stochastic process, with the timing of synaptic events being governed by probability (review in Kavalali, 2015). The distribution of the IEIs of such events is without any periodicity (Cohen et al., 1974). In the auditory system, such spontaneous random firing is re-organized to be orderly (e.g., phase-locking) when a low frequency sound stimulus is given, causing neurons to fire APs at a certain phase of the sinusoidal waveform of the sound (review in Heil and Peterson, 2017). The synaptic responses underlying the generation of the timely precise spikes are mediated primarily by fast ionotropic glutamate receptors (review in Leão, 2019). In contrast, metabotropic glutamate receptors (mGluRs), as subfamily 3 G-protein-coupled receptors (GPCRs), typically mediate much slower-onset and longer-lasting modulatory effects on neuronal properties (review in Niswender and Conn, 2010). Thus, mGluR-mediated responses are usually not associated with fast cycle-to-cycle modulation that underlies temporally patterned neural activities.

However, a number of studies have shown unconventional actions of some GPCRs on neuronal spiking activities. The slow responses of GPCRs could constrain the ability of neural networks in generating inputs at certain frequency, forming rhythmic oscillations. In a number of neural pathways such as the motor circuits in the spinal cord and brainstem, activation of mGluRs results in bursting AP firing and rhythmic neural activities (review in Nistri et al., 2006), and modulates rhythmic motor patterns (review in El Manira et al., 2002). Activation of group I mGluRs (mGluR I, including mGluR1 and mGluR5) enhances spontaneous rhythmic bursts when synaptic inhibition is blocked in the spinal cord, and blocking mGluR I conversely lengthens the locomotor cycle period (Taccola et al., 2004). Furthermore, activation of presynaptic mGluR I causes membrane depolarization and produces rapid fluctuations of intracellular Ca2+ concentration, the latter of which is believed to generate rhythmic locomotion (Takahashi and Alford, 2002).

In the auditory brainstem, mGluRs are widely expressed during development and some mGluRs persist after hearing onset (review in Lu, 2014). MNTB, a critical component involved in sound localization processing in the auditory brainstem, receives its major excitatory inputs via calyxes from bushy cells in the contralateral anteroventral cochlear nucleus (AVCN) and non-calyceal inputs from unknown sources, and inhibitory inputs from multiple sources including the ipsilateral ventral nucleus of the trapezoid body (VNTB) (review in Joris and Trussell, 2018). Multiple mGluRs exert neuromodulation at MNTB synapses (review in Kopp-Scheinpflug et al., 2011). New analyses of the data from our previous studies, in which we reported mGluR I-mediated enhancement of sIPSCs (Curry et al., 2018) and sEPSCs (Peng et al., 2020), revealed that in a subpopulation of MNTB neurons, activation of mGluR I induced temporally patterned AP-dependent transmitter release. A global mGluR5 knockout mouse model was used to examine the contribution of mGluR5 to this phenomenon. To test the hypothesis that temporally patterned spike activity evoked by mGluR I activation in the presynaptic cells may underly the patterned transmitter release in MNTB, cell-attached recordings were used to examine the effects of mGluR I in VNTB neurons and AVCN bushy cells. Immunocytochemistry was used to examine the subcellular localization of mGluR1 and mGluR5 in the VNTB-MNTB pathway.

留言 (0)

沒有登入
gif